Mechanisms of resistance in breast cancer are not yet well defined, notes Richard Finn, MD. Findings from the BOLERO-2 study suggest that the PI3K pathway could play a role in resistance. Additionally, findings from the NeoALLTO study found that PIK3CA mutations were associated with lower pathologic complete response rates for individual patients with HER2-positive breast cancer. However, at this time, a clear cause of resistance is not yet defined.

Early phase studies have identified several molecular abnormalities, such as ESR1 mutations, that are associated with endocrine resistance, providing rationale for conducting prospective studies. However, Ruth O’Regan, MD, and Lee Schwartzberg, MD, agree that although ER mutations are interesting, they are not yet ready for primetime.

Nevertheless, endocrine therapy should be used cautiously in patients with ER mutations, Kim Blackwell, MD, advises. Some studies have suggested that certain endocrine therapies could still be effective in patients with these mutations; however, the responses are less robust. This has been seen with 500-mg fulvestrant and with the combination of everolimus and exemestane in the BOLERO-2 study, Blackwell notes.

Building on these observations, the BELLE-2 and -3 studies are assessing the oral pan-PI3K inhibitor buparlisib in combination with fulvestrant for various populations of patients with aromatase inhibitor resistant breast cancer. These studies will be important, as prospective data are currently lacking, notes Finn.